JPS6049633B2 - Method for producing 2,4-diamino-5-benzylpyrimidine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 2,4-diamino-5-benzylpyrinomidine.

It is known that 2,4-diamino-5-benzylpyrimidines have antibacterial and/or antimalarial activity and that such activity can be activated by using pyrimidines together with sulfonamides.

One very useful pyrimidine is commonly Trimet.
hOprim[2,4-diamino-5-(3″,4″,
The activity obtained with this compound is such that it has been used with considerable success in the treatment of various parasitic diseases with sulfonamides such as sulfamethoxazole. It is.2
, 4-diamino-5-benzylpyrimidine are known.

Most important ones (e.g. British Patent No. 957797)
No. Specification, No. 1133766, No. 114265
4 and 1261455) use appropriately substituted benzaldehydes and β-monosubstituted probionitriles as starting materials. These are reacted with each other under conditions specified in their respective patent specifications to obtain an intermediate, which is then cyclized with guanidine to form the desired 2,4-
diamino-5-benzylpyrimidine. Although these processes, particularly those of GB 1 133 766 and GB 1 261 455, have produced such pyrimidines in reasonable yields, unfortunately there is little flexibility in how the intermediates are obtained. The industrial operation of these processes could therefore be jeopardized in the event of a shortage of one of the starting materials. The object of the present invention is to provide a process for cyclization with guanidine to obtain 2,4-diamino-5-bendipyrimidine.

Using readily available starting materials. The object of the present invention is to provide a method for obtaining 2,4-diamino-5-benzylpyrimidine in continuous high yield without requiring any unusual equipment or reaction conditions. The novel intermediates used in the process of the invention have the formula (
In the benzyl cyanoacetal of 1), R1, R2 and R3 are the same or different and each is a hydrogen atom, an alkoxy group or an alkyl group; R4 is an alkoxycarbonyl group or an aldehyde group; R5 is an alkyl group and each alkyl or alkoxy group is 1-
It has 4 carbon atoms.

R1, R2, and R3 are preferably methyl or methoxy groups or hydrogen atoms. Specifically, R1, R2 and R3 represent phenyl rings with methoxy groups at the 3-, 4- and 5-positions, or methoxy groups at the 3- and 4-positions, or methyl groups at the 2-position. 4
- and 5- positions are substituted with methoxy groups. A preferred example of R4 in the case of an alkoxycarbonyl group is a methoxy, especially an ethoxycarbonyl group.
R5 is conveniently a methyl or ethyl group.

Particularly preferred benzylcyanoacetals are R1, R2
and R3 is 3,4,5-trimethoxy, R4 is ethoxycarbonyl or aldehyde group; and R5 is methyl or ethyl group.

These benzylcyanoacetals are important antibacterial Tr
It is a preferred intermediate for the synthesis of jmethOpprim. Therefore, the present invention combines 2,4-diamino-5-benzylpyrimidine of formula (X[) (in which R1, R2 and R3 are defined above) with benzylcyanoacetal of formula (1) (defined above) and guanidine. A method is provided for producing the compound by reacting the compound in a solvent which is compatible with and capable of dissolving both reactants.

The solvent that can be used in this reaction is preferably an alcohol having 1 to 4 carbon atoms, such as ethanol, and the reaction itself is about 1 to 3 carbon atoms.
It is preferable to carry out the reaction at a reflux temperature between 0.011V and 0.011V.

When R4 in the benzylcyanoacetal of formula (1) is an alkoxycarbonyl group, it is desirable to carry out the reaction in the presence of an additional base such as caustic potassium. Further advantages of the invention will become apparent from the following description of embodiments of the invention.

This embodiment does not in any way limit the scope of the invention. Example 1 (Reference example) α-dimethoxymethyl-α-formyl-β-(3,4
, 5-trimethoxyphenyl)probionitrile A solution of α-formyl-β-(3,4,5-trimethoxyphenyl)probionitrile (17.2y10.069 mol) in trimethyl orthoformate (100ml) was continuously added with methanol. The mixture was heated at reflux for 3 hours using a steam jacketed column for complete removal.

The solution was cooled and most of the excess orthoformate was removed in vacuo. The residual oil was taken up in ether (100ml) and crystallization began almost immediately. The mixture was filtered to give pale yellowish brown crystals (9.411142%, M.P.ll
7-12rC) was obtained. Colorless needle-shaped crystals of α-dimethoxymethyl-α-formyl-β(3,4,5-trimethoxyphenyl)probionitrile were obtained by recrystallization from cyclohexane-chloroform: M. p. ll8-122
℃：2250C77! -1 (C King N) and 1738c
Ir Bandoni Nmr (CDCl3) of m-1 (CHO)
δ3.15 (Sl2, Ar-CH2-C) ~ 3.57 and 3.62 (Single wire, 6, CH (0C), 3.87
(Sl9, -C6H2(0CH3)3), 4.50(S
ll. Cdan(0CH3)2), 6.53 (Sl2, aromatic H), and 9.53 (S.l..CHO). Cl6
Analysis calculation value of H2lNO6: Cl59.43:Hl6.
55:Nl4.33O Experimental value: 59.44:Hl6.6
O:Nl4.33. Example 2 (Reference example) Production of α-diethoxymethyl-α-formyl-β-(3,4,5-trimethoxyphenyl)probionitrile Same as Example 1 except that triethyl orthoformate is used instead of trimethyl orthoformate. Using the same method, α-diethoxymethyl-α-formyl-β-(3,4,5-trimethoxyphenyl)probionitrile (78%, M.p.l.
O9-115°C) was obtained.

An analytical sample (M.P.l.
17-12rC) was obtained. Analytical calculation value of Cl6H2lNO6: Cl6l. 52:Hl7. l7:Nl3.99.
Experimental value: Cl6l. 3l: Hl 7.2l: Nl 3.87
. Example 3 (Example) Production of 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine α-diethoxymethyl-α-
Formyl β-(3,4,5-trimethoxyphenyl)probionitrile (35.1y10.10 mol) was added to an ethanol solution of guanidine (guanidine hydrochloride 0.35 mol).

The mixture was heated at reflux for 6.5 hours while allowing sufficient boiling off of the ethanol to raise the reaction temperature to 85°C. The dark solution was allowed to cool overnight. The mixture was filtered and the solid was washed with cold ethanol and dried to give the crude product (24.4y, 8
4.1%). Purification was carried out by dissolving the crude product in a hot acetic acid aqueous solution and reprecipitating it with concentrated ammonium hydroxide. The precipitate was washed twice with water and once with cold acetone, dried, and
4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine (19.5y167.2%), M. p.
197-198°C (determined by Nmr) was obtained. The acetone was concentrated in vacuo and additional trimethoprim (2.5 g, 8.6%, M.p.l 94-196°C) was added, albeit with a slightly lower purity.
) was obtained by drying. Example 4 (Reference example) α-carbuethoxyα-diethoxymethyl-β-(3
, 4,5-trimethoxyphenyl)probionitrile A solution of ethyl 3,4,5-trimethoxybenzylcyanoacetate (14.7y) in triethyl orthoformate (100 mt) was steamed to continuously remove the ethanol. It was heated to reflux for one hour using a jacketed column.

The solution was cooled and most of the excess orthoformate was removed in vacuo. The obtained crystals were washed with ether and dried to give α-carnobethoxy-α-diethoxymethyl-β-(
Colorless crystals of 3,4,5-trimethoxyphenyl)probionitrile (16.3y182%), M. p. 9l(C
DCl3) δ1.13, 1.20 and 1.32 (triplet, 9, Cd.CH2O-), 3.15 (s, 2
, Ar-gate Cll2-C), 3.4-4.0 (Ml4,
Ml4, CH3CU2-0), 3.85 (Sl9, -C
6H2-(0Cdan3)3), 4.13(Ql2, CH3
C day, -0C0), 4.80(Sll, -C day (0Et
)2) and 6.55 (Sl2, aromatic H) were obtained. )
Analysis calculation value of C2OH29NO7: Cl6O. 74:H
l7.39:Nl3.54.

Experimental value: Cl6O. 56: Hl7.33: Nl3.64
.

Example 5 (Example) 2,4-diamino-5-(3,4,5-
Preparation of α-carbethoxyα-diethoxymethyl-β-(3,4,5-trimethoxyphenyl)probionitrile (7.9y, .
0.02 mol) and an equivalent amount of caustic potassium in ethanol (5
0ml) The solution was heated to reflux for 1 hour.

Guanidine (a). 07 mol) of ethanol (50 ml
) solution and started refluxing again. Some of the ethanol was boiled off and the reaction temperature was raised to 85°C. Approximately 2
After refluxing, the mixture was cooled and the product was filtered and washed with ethanol. The crude product was purified by treatment with a hot aqueous acetic acid solution and reprecipitation with ammonium hydroxide. The yield of purified trimethoprim (M.p.l 97-198°C) was 3.6 Da (
62%), and its identity was confirmed by NMR spectrum. Example 6 (Reference example) Production of ethyl 3,4,5-trimethoxybenzyl cyanoacetate Metallic soda (17.7y10.77y one atom) was heated over 3 hours with 10409 (9
．． 2 mol) of ethyl cyanoacetate.

The temperature was maintained at 22-26°C in a water bath. The resulting milky white suspension was stirred for an additional hour, cooled to 10 liters and treated with 3,4,5-trimethoxybenzyl chloride (83.
2 Da, 0.384 mol) was added in 2 hour portions. The reaction mixture was then stirred at ambient temperature for a specific time. The reaction mixture was cooled to 19-20 temperature and added with 960 ml of acetic acid aqueous solution (
V/■) was added. Benzene (1200ml) was added and the layers were separated after thorough mixing. The aqueous layer was extracted with 2 x 540mt benzene. Combine benzene extract, 100
Wash with 0ml of water and rinse with magnesium sulfate. Dry on a rack.
Benzene was removed using a rotary dryer and a 500° water bath. The residue was then 0.2TIr! n mercury pressure and 10
Excess ethyl cyanoacetate was removed by vacuum distillation in a 5-110 mm oil bath. Crude ethyl 3,4,5-trimethoxybenzylcyanoacetate! Tate's yield is 107.2y.
(95.5%). Example 7 (Reference example) Ethyl 3,4
Preparation of ,5-trimethoxybenzylcyanoacetateTrimethoxybenzaldehyde was combined with ethylcyanoacetate and the product (94.6%) was prepared as described in British Patent No. 14
Catalytic hydrogenation according to the method of 06307 gave ethyl 3,4,5-trimethoxybenzylcyanoacetate (91.5%).

Example 8 (Reference Example) Production of diethoxymethyl acetate Acetic anhydride (550y), formic acid (275y) and trimethyl orthoformate (740y) were prepared by DeWolfe.
The reaction was carried out as described in Synthesis II 974, 153-1n (weighed 5 times).

The product has a float point of 77-78°C in 25Tf0n mercury and a temperature of 5
The yield was 4.5%. Example 9 (Reference example) α-carbuethoxy α-diethoxymethyl-β-(3,4,5
Preparation of -trimethoxyphenyl)probionitrile Ethyl 3,4,5-trimethoxybenzylcyanoacetate (5y) was mixed with diethoxymethyl acetate (15q) and heated at 95°C overnight.

The mixture was cooled and ether-hexane (11) (25
m1) was added to crystallize. The product was filtered and dried under reduced pressure to yield 4.9y (73%) of a white solid M. p. 95-97
℃ was obtained. Example 10 (Reference example) α-carbuethoxyα-diethoxymethyl-β-(3
, 4,5-trimethoxyphenyl)probionitrile 3,4,5-trimethoxybenzylcyanoacetic acid monohydrate (5f) was mixed with trimethyl orthoformate (42ml
) and heated under reflux for 21 hours.

The solvent was removed under reduced pressure and the resulting oil was crystallized from ether-hexane to give a white solid (4.4y) (63%), M.I.
p. A temperature of 95-96.5°C was obtained. Example 11 (Reference example) Ethyl 2-cyano 4″, 5″-dimethoxy 2″-
Preparation of methyl cinnamate 4,5-dimethoxy-2-methylbenzaldehyde (36y), ethylcyanoacetate (22.6y), piperidine (2y) and acetic acid (
A 125 ml benzene mixture of 0.7 g) was adapted to azeotropic removal of water and heated under reflux for 5 hours.

The mixture was cooled, chloroform (400ml) was added and the resulting solution was diluted with 2X200ml water, 200ml (7)0
．． 5N hydrochloric acid, 200ml saturated soda bicarbonate, 200ml
Extracted with 1 portion of water and dried (MgSO4). The volatiles were removed under reduced pressure and the remaining yellow solid was washed with cold methanol.
Dry under reduced pressure to give 51.5y (94%) of the title compound M
．． p. l42-144yC was obtained. Example 12 (reference example) α
Preparation of ethyl-2-cyano-4'',5''-dimethoxy-2''-methylcinnamate (30y) and 5% palladium on carbon (2y)
The 50 ml ethanol mixture was shaken under a 50 pSi atmosphere of hydrogen gas to absorb slightly more than 1 equivalent (15%) of hydrogen gas.

The catalyst was filtered off, the volatiles were removed under reduced pressure and the residual yellow clear oil was left to solidify at -5°C: M. p. 39
~40'C1 yield 27.6y (90%). Example 13 (Reference example) α-carbuethoxy α-diethoxymethyl-β-
Preparation of (4,5-dimethoxy-2-methylphenyl)probionitrile α-carbethoxyβ-(2-methyl-4,5-dimethoxyphenyl)probionitrile (1
4.7q) to triethyl orthoformate (100m
1) The mixture was heated under reflux for an hour with a vapor cooling condenser attached.

Triethyl orthoformate was removed under reduced pressure and 10
0ml of 1°1 ether-hexane was added. -5℃
crystals formed after cooling? filtered, washed with 1°1 ether-hexane (100ml) and dried under reduced pressure to give 16.3q
(84%) of a tan solid M. p. 84-86 to obtain C. Example 14 (Example) Preparation of 2,4-diamino-5-(4,5-dimethoxy-2-methylbenzyl)pyrimidine (0rmet0prim) α-carbuethoxyα-diethoxymethyl-β-(4
, 5-dimethoxy2-methylphenyl)probionitrile (3.9110.01 mol) and an equivalent amount of caustic potassium in ethanol (70 ml) were heated under reflux for 1 hour.

Guanidine (4). 035 mol) of ethanol (50 m
1) Add the solution and re-reflux. Reaction temperature is 85℃
Ethanol was boiled off until . After 2 hours at reflux, the mixture was cooled and the product was filtered and washed with ethanol to give an almost white solid at 2.57V (94%). After purification as described in Example 5, the product was dried under reduced pressure to give a white solid M. p. 23l-233°C was obtained. Example 15 (Reference Example) Production of ethyl-2-cyano 3',4''-dimethoxycinnamate 3,4-dimethoxybenzaldehyde (49
．． 8′), 175 ml of ethyl cyanoacetate (33.9y), piperidine (3y) and acetic acid (1.1y)
The benzene mixture was adapted to azeotropic removal of water and heated to reflux overnight.

The product was isolated as described in Example 11 and yielded 67.4y (86
%) of pale yellow solid, M. p. 149-150°C was obtained.
Example 16 (Reference example) Production of α-carbethoxyβ-(3,4,-dimethoxyphenyl)probionitrile Ethyl-2-cyano3
″,4″-dimethoxycinnamate (26.1q) 1
50ml ethanol and 5% palladium on carbon (2f)
mixed with.

The mixture was shaken under a hydrogen atmosphere (50 psi) until slightly more than 1 equivalent (10%) of hydrogen gas was absorbed.
The catalyst was removed and the volatiles were removed under reduced pressure to 24.5 f(
93%) of a yellow oil was obtained. The structure was confirmed by NMR spectrum. Example 17 (Reference example) α-carbuethoxyα-diethoxymethyl-β-(3
,4-dimethoxyphenyl)probionitrile production α
A mixture of monocarbethoxy β-(3,4-dimethoxyphenyl)probionitrile (10g) and diethoxymethyl acetate (30y) was heated at 95°C for 20 hours.

Volatiles are removed under vacuum pump pressure and the remaining 13.4V
(94%) of an almost colorless oil was left at -5°C to produce a white solid M. p. Solidified at 62-65°C. Example 18 (Example) Preparation of 2,4-diamino-5-(3,4-dimethoxybenzyl)pyrimidine (Diaveridine) α-carbethoxyα-diethoxymethyl-β-(3,4-dimethoxyphenyl)propioni7tolyl (3.75q
) and an equivalent amount of caustic potassium in ethanol (70 ml) were heated to reflux for 1 hour.

Claims (1)

[Claims] 1 Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [R^ in the formula
1, R^2 and R^3 are the same or different, each is a hydrogen atom, an alkoxy group or an alkyl group, and R^
4 is an alkoxycarbonyl group or an aldehyde group, and R^5 is an alkyl group, each alkyl or alkoxy group having 1 to 4 carbon atoms) and guanidine as both reactants. 2,4-diamino-5-benzylpyrimidine of formula (X I)▲There are mathematical formulas, chemical formulas, tables, etc.▼(X I), which is characterized by being compatible and reacting in a soluble solvent. Production method. 2. The method according to item 1, wherein the solvent is a C_1 to C_4 alkanol. 3. The method according to item 2, wherein the alkanol is ethanol. 4. The method according to any one of Items 1 to 3, wherein the reaction is carried out at reflux temperature for 1 to 30 hours. 5. The method according to any one of items 1 to 4, wherein the reaction is carried out in the presence of an additional base when R^4 is an alkoxycarbonyl group. 6. The method according to item 5, wherein the base is caustic potash.